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This Article Full Text Full Text (PDF) All Versions of this Article: 295/5/G1122    most recent 90430.2008v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Wang, M.-L. Articles by Wu, G. D. PubMed PubMed Citation Articles by Wang, M.-L. Articles by Wu, G. D.

INFLAMMATION/IMMUNITY/MEDIATORS

Immune-mediated signaling in intestinal goblet cells via PI3-kinase- and AKT-dependent pathways

¹Division of Gastroenterology, University of Pennsylvania School of Medicine and ²Division of Gastroenterology, Hepatology, and Nutrition, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania; and ³Stowers Institute for Medical Research, Kansas City, Missouri

Submitted 14 July 2008 ; accepted in final form 25 September 2008

In the intestinal epithelium, activation of phosphatidylinositol 3-kinase (PI3-kinase)/AKT pathways, via growth factor-mediated signaling, has been shown to regulate cell proliferation and inhibit apoptosis. An immune-activated receptor critical for Th2 immune responses, IL-4R can also activate PI3-kinase via insulin receptor substrate (IRS)-dependent signaling. Here, using the intestinal goblet cell-specific gene RELMβ, we investigated the effect of PI3-kinase activation via Th2 immune responses on the goblet cell phenotype. IL-13 stimulation activated PI3-kinase and AKT signal transduction in LS174T cells. Not only did pharmacological inhibition of PI3-kinase and AKT1/2 inhibit RELMβ induction by IL-13, but AKT inhibition also significantly reduced constitutive basal expression of RELMβ, a response reproduced by the simultaneous pharmacological inhibition of both epidermal growth factor receptor and IGF-I receptor signaling. In vivo, the disruption of phosphatase and tensin homolog deleted on chromosome 10 (PTEN), an inhibitor of PI3-kinase activation, led to the activation of RELMβ expression in the small intestine. Furthermore, induction of an intestinal Th2 immune response by infection with a small intestinal nematode parasite, Heligmosomoides polygyrus, led to enhanced epithelial cell proliferation, activation of AKT as demonstrated by the loss of Foxo1 nuclear localization, and robust induction of RELMβ expression in wild-type, but not IL-4R knockout, mice. These results demonstrate that Th2 immune responses can regulate goblet cell responses by activation of PI3-kinase and AKT pathways via IL-4R.

phosphatidylinositol 3-kinase; epithelium; intestine